This application summarizes the research and career plan proposed by Dr. Gerald D. Frank, which focuses on uncovering novel vascular signaling pathways and mechanisms utilized by protein kinase C (PKC) delta activated by vascular pathogens that lead to vascular remodeling. Identifying key PKC delta activation mechanisms and its precise signaling sequence involved in the vascular remodeling process is very important for understanding development of vascular diseases and establishing new strategies and therapies toward PKC delta-dependent vascular signaling and function activated by vascular pathogeng. A critical component of vascular diseases may involve intracellular mechanisms. Vascular pathogens such as angiotensin II, platelet-derived growth factor and reactive oxygen species activate key protein kinases promoting cell growth and migration of vascular smooth muscle cells (VSMCs), thereby contributing to the development of cardiovascular diseases. It is likely that key signal transduction cascades involved in functional responses to vascular pathogens converge at the level of PKC activation since it is one of the earliest signaling events induced by them. We have shown that PKC delta is linked to the activation of various tyrosine kinases in VSMCs. Therefore we hypothesized that PKC delta acts as a unique signal sensing molecule and is required for activation of specific downstream signal transductions in VSMCs critical for vascular remodeling. Specific Aim #1 of this application is to determine the molecular mechanism responsible for integrated PKC delta activation induced by key vascular pathogens in cultured VSMCs. Specific Aim #2 is to determine the pathogen-induced protein-protein interactions of PKC delta with various signaling molecules in VSMCs and to identify the critical downstream signal transduction of PKC delta. Specific Aim #3 will determine the functional downstream role(s) of PKC delta activation essential for VSMC growth and migration. This research will utilize various new experimental methodology and expertise in biochemistry, physiology, vascular biology, structural biology and cell and molecular biology. The Biochemistry Department at Vanderbilt University School of Medicine is an excellent and ideal institution to develop the independent academic career of the applicant whose long-range goal is to elucidate the activation mechanisms and functions of specific PKC isoforms in VSMCs underlying development of vascular remodeling.